Medical devices are known which deliver drugs by iontophoresis, a process by which an electric field is used as a driving force to move a drug into a subject. This technique typically requires two or more electrodes for creating an electric field as well as a drug that carries a net electrical charge at the local physiological pH.
Medical devices are also known which rely on electroporation to enhance drug delivery to cells. The electroporation method uses short, high-voltage pulses to create transient pores in the cell membranes or in organelles within the cells. This transient, permeabilized state can be used to load cells and organelles with a wide variety of therapeutic agents, for example, genes, proteins, small molecule drugs, dyes, tracers, and so forth. Electroporation has already proven to be effective in both chemotherapy and gene therapy, including vascular gene therapy and endovascular treatment. See, e.g., Dean, “Electroporation of the Vasculature and the Lung,” DNA and Cell Biology, 22 (12), 2003, p. 797; Yang, “Imaging of Vascular Gene Therapy,” Radiology 2003; 228:36-49; Duncan, “The Dawning Era of Polymer Therapeutics,” Nature Reviews, Volume 2, May 2003, p. 347; Lavasanifar et al., Advances Drug Delivery Reviews, 54 (2002) 169, each of which is incorporated by reference in its entirety.
Unfortunately, the effective in vivo electroporation of vascular tissues is commonly hindered by anatomy, which restricts electrode placement and thus options for optimized electric field distribution.
For example, referring now to FIG. 1A, it is known to provide first and second electrodes E1 and E2 within a porous balloon 110 of a catheter 100. The catheter 100 is inserted into a body lumen such as the lumen formed by a blood vessel wall 150, for example, over a previously inserted guide wire E1, and placed at the desired location within the lumen. The porous balloon 110 is inflated so that blood flow is transiently obstructed, and a drug solution is infused into the balloon. Because of the porous nature of the balloon, the drug can be delivered to the vessel wall. The electrode system uses the guide wire E1 as one electrode and an internal wrapped wire E2 contained within the balloon 110 as the second electrode. When a voltage is applied between the two electrodes, an electric field develops, causing electroporation of the surrounding vessel wall 150 and delivery of drug to cells within the vessel wall.
Unfortunately, such an electrode configuration, in which both electrodes are positioned within the vessel lumen, does not provide an electric field in which a vector of the field (e.g., a primary or secondary field vector) is pointed toward the vessel wall.
Other electrode configurations have been developed to address this issue. For example, referring now to FIG. 1B, it is also known to deliver a molecule such as DNA by electroporation to a vessel wall 150 using a catheter 100 having electrodes E1 and E2 (e.g., two stainless steel electrodes) positioned outside of the vessel wall 150, on opposite sides of the vessel wall 150 (i.e., the field is applied from the electrodes at the adventitial surface of the vessel 150). In use, the catheter 100 is positioned in the vessel 150, balloons 115a, 115b are inflated, and DNA is released into the volume between the balloons 115a, 115b. Once the lumen is filled with DNA, square-wave electric pulses are delivered to the electrodes E1, E2. Unlike the electrode configuration of FIG. 1A, by placing the electrodes on opposite sides of the adventitial surface of the vessel 150, an electric field is provided in which a vector of the field is pointed in the direction of the vessel wall. However, such a procedure is more complicated than that associated with FIG. 1A, as the two electrodes must be positioned outside of the vessel 150. The construction as described in FIG. 1B also has the disadvantage that the drug is provided within a solution and is able to freely flow in any direction. Non-homogeneity of the electric field will therefore cause a non-homogeneous distribution of the drug. Using paclitaxel as a specific example, it is known that the dose for this drug has to be within a relatively narrow window to be effective, which is made difficult by a system that uses a fluid carrier.
Another disadvantage of currently used electroporation delivery systems such as those above is the need for an additional lumen and ports to accommodate a pressurized drug infusion.
Drug delivery in conjunction with a balloon coated with a drug loaded hydrogel has also been attempted. However, up to 65% of the drug was washed from the balloon within 60 secs of exposure to flowing blood. Noel Caplice and Robert Simari, “Gene Transfer for Coronary Restenosis,” Novel Revascularization Strategies, Current Interventional Cardiology Reports 1999, 1: pp. 157-164, which is incorporated by reference in its entirety.
The above and other drawbacks of prior devices are addressed by various aspects of the present invention, in which various improved devices are provided for delivery of therapeutic agents based on electric field effects (i.e., delivery is electrically assisted), such as iontophoresis, electroporation, or both.